Surfactant, and an emulsion-type cosmetic composition and a liposome containing said surfactant

ABSTRACT

The invention provides a surfactant comprising at least one trehalose-6-fatty acid ester selected from those represented by the following formula:  
                 
wherein R represents a saturated or unsaturated acyl group having 8-22 carbon atoms, and may have a hydroxyl group or other substituents, and an emulsion-type cosmetic composition comprising said surfactant and a water-soluble polymer. The surfactant of the invention has excellent surface activity and safety. Also, the emulsion-type cosmetic composition has excellent long-term storage stability and sensory properties, has no irritation to skin, and gives beautiful appearance with fine surface texture. Further, the invention is a liposome having a membrane wall composed of trehalose fatty acid ester. Said liposome has excellent chemical and physical stabilities such as long-term storage stability.

FIELD OF THE INVENTION

The present invention relates to a surfactant which has excellentsurface activity and safety.

The invention also relates to a detergent with excellent safety,containing the surfactant.

The invention further relates to an emulsion-type cosmetic compositionwith excellent emulsion stability, safety to skin and sensoryproperties, containing the surfactant.

BACKGROUND OF THE INVENTION

A number of compounds are known as surfactants and used in manyapplications. However, most of those surfactants irritate skin when theyare used in cosmetics, such as shampoos, rinses, soaps and othercosmetic compositions, which contact with a human body directly.Therefore, lower irritating surfactants have been desired.

In many emulsions use is made of nonionic surfactants having apolyoxyethylene chain, anionic surfactants such as fatty acid soaps,cationic surfactants or ampholytic surfactants. However, there was aproblem that emulsion-type cosmetic compositions with those syntheticsurfactants generally tend to irritate skin. Also, even with nonionicsurfactants which are said to be less irritating, most of them fitpoorly to skin because of their polyoxyethylene chains.

On the other hand, alkylesterified sugars are nonionic surfactants whichhave been used widely in foods, cosmetics and the like. Among others,sucrose alkylesters in which sucrose constitutes a sugar skeleton areused widely and seen in many publications (Japanese Patent ApplicationLaid Open No. 56-55306/1981). However, those are insufficient in sensoryproperties and long-term storage stability. Also, it is known to use, asa surfactant, trehalose-6,6′-dialkylester in which a trehalosederivative constitutes a sugar skeleton (Japanese Patent ApplicationLaid Open Nos. 60-25819/1985 and 62-91236/1987). Those are insufficientin emulsifiability.

Synthesis of trehalose fatty acid ester are reported in Chem. Phar.Bull., 30 (4) pp 1169-1174, (1982), where synthesis of6-stearoyl-trehalose and 6,6′-distearoyl-trehalose and the analysis ofthem using NMR, etc. are described. Those esters are reported to haveanti-tumor activity against Ehrlich ascites tumor in mice. There is nodescription or suggestion that they show properties as a surfactant. Anemulsion-type anti-tumor agent is known in which a specific emulsifiercomposition is combined with trehalose-6,6′-difatty acid ester as ananti-tumor agent in order to solve a disadvantage that the ester isdifficult to dissolve in water (Japanese Patent Application Laid OpenNo. 61-289038/1986).

In consideration of surface activity, foamability, washing ability andso forth for a surfactant, the presence of a single lipophilic moiety issaid to be preferred. For example, glucose fatty acid monoester isreported in Japanese Patent Application Laid Open No. 03-157349/1991.However, this has a disadvantage that a stable emulsion can not beobtained due to its weak hydrophilicity.

DISCLOSURE OF THE INVENTION

A purpose of the invention is to provide a surfactant that has excellentsurface activity and safety.

Another purpose of the invention is to provide a detergent that hasexcellent safety.

A further purpose of the invention is to provide an emulsion-typecosmetic that has low irritation to skin, long-term storage stability,excellent sensory properties and beautiful appearance with fine surfacetexture.

The present invention is a surfactant containing one or more oftrehalose-6-fatty acid esters represented by the following formula:

wherein R represents a saturated or unsaturated acyl group having 8-22carbon atoms, and may have substituents such as a hydroxyl group.

One preferred embodiment of the invention is a surfactant containing6-(10-undecylenyl)-trehalose represented by the following formula:

Another preferred embodiment of the invention is a surfactant containing6-lauroyl-trehalose.

Further, another preferred embodiment of the invention is a surfactantcontaining 6-stearoyl-trehalose.

Also, the invention is a detergent characterized in that it contains asurfactant containing one or more of trehalose-6-fatty acid estersrepresented by the following formula:

wherein R is a saturated or unsaturated acyl group having 8-22 carbonatoms, and may have substituents such as a hydroxyl group.

Further, the invention is an emulsion-type cosmetic compositioncharacterized in that it contains one or more of trehalose-6-fatty acidesters represented by the following formula:

wherein R is a saturated or unsaturated acyl group having 8-22 carbonatoms, and may have substituents such as a hydroxyl; and

a water-soluble polymer.

BEST MODE OF THE INVENTION

The trehalose-6-fatty acid ester of the invention can be obtained by acondensation reaction of trehalose with a fatty acid or by an esterinterchange reaction between trehalose and a fatty acid ester.

Examples of the fatty acid or fatty acid ester which can be used in theinvention include synthetic fatty acids and esters thereof, naturalfatty acids, such as soybean fatty acid, beef tallow, cotton seed oil,olive oil, palm oil and so forth, and fatty acid esters thereof withlower alkyl groups, which esters are obtained in any conventionalmethod.

Trehalose which can be used in the invention may be α, α-trehalose, α,β-trehalose, β, β-trehalose or mixtures thereof.

The trehalose-6-fatty acid of the invention can be obtained in any usualmethod of producing sucrose alkyl esters, as described in U.S. Pat. Nos.2,893,990 and 3,963,699, Japanese Patent Application Laid Open laid Nos.36-21717/1961 and 53-6130/1978, all of which are incorporated herein byreference.

The trehalose-6-fatty acid ester is obtained as a main reaction productin these methods. In some cases, there are contained small amounts ofunreacted trehalose and trehalose-6,6-fatty acid diester as aside-reaction product. The trehalose-6-fatty acid ester may be purifiedin a conventional manner before used, if desired. However, thetrehalose-6-fatty acid may be used together with small amounts ofunreacted trehalose and trehalose-6,6′-fatty acid diester, because thetrehalose-6-fatty acid can exhibit surface activity even in the presenceof them.

The trehalose-6-fatty acid ester used in the invention is preferablythose in which a fatty acid radical, i.e. an acyl group, has a linear orbranched, saturated alkyl or alkenyl group having 8-22 carbon atoms.Examples of those include trehalose monocaprylate, trehalosemonononanoate, trehalose monocaprate, trehalose monoundecanoate,trehalose monolaurate, trehalose monomyristate, trehalose monopalmitate,trehalose monostearate, trehalose monoarachidate, trehalosemonobehenate, trehalose monoundecylenate, trehalose monooleate,trehalose monolinoleate, trehalose monolinolenate, trehalosemonoisostearate, trehalose monohydroxystearate, and trehalosemonoricinoleate. One or more from these trehalose-6-fatty acid esterscan be used in the invention.

The surfactant of the invention preferably contains one or more selectedfrom 6-(10-undecylenyl)-trehalose, 6-lauroyl-trehalose and6-stearoyl-trehalose.

The surfactant of the invention has excellent surface activity andsafety to skin and also may be used as an emulsifier in foods.

The skin or hair washing agent detergent of the invention preferablycontains one or more of the trehalose-6-fatty acid ester in an amount of1-50 wt. %, particularly 10-35 wt. %. It may further contain othersurfactants.

The cosmetic composition of the invention contains one or more of theabove trehalose-6-fatty acid ester and a water-soluble polymer. Thecontent of the above trehalose-6-fatty acid ester in the cosmeticcomposition is preferably 0.01-20 wt. %, particularly 0.1-10 wt. %,based on the total weight of the cosmetic composition. If the content isless than 0.01 wt. %, the emulsion stability of the cosmetic compositiontends to decrease during its storage. On the other hand, if it is morethan 20 wt. %, it is difficult to obtain fine feeling in use.

The water-soluble polymer used in the invention may be generally any ofthose used in cosmetic compositions or pharmaceutical bases. Examples ofthe water-soluble polymer include guar gum, roast bean gum, queensseed,carageenan, galactan, arabic gum, tragacanth, pectin, mannan, starch,xanthan gum, dextrin, succinoglucan, curdlan, gelatin, casein, albumin,collagen, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, carboxymethyl cellulose, methylhydroxypropylcellulose, soluble starch, carboxymethyl starch, methyl starch,propyleneglycol alginate, salts of alginic acid, polyvinylalcohol,polyvinylpyrrolidone, polyvinylmethylether, carboxyvinyl polymers,sodium polyacrylate, polyethyleneglycol, ethylene oxide/propylene oxidecopolymers, cationated cellulose, sodium chondroitin sulfate, and sodiumhyaluronate. These water-soluble polymers may be used alone or incombination.

The content of the above water-soluble polymer is preferably 0.001-40wt. %, particularly 0.01-20 wt. %, on the basis of the total weight ofthe cosmetic composition. If the content is less than 0.001 wt. %, theemulsion stability of the cosmetic composition tends to decrease duringits storage. On the other hand, if it is more than 40 wt. %, it isdifficult to obtain fine feeling in use.

The cosmetic composition of the invention may contain one or more oilsubstances that can usually be used in cosmetic compositions orpharmaceutical bases, if necessary, such as hydrocarbons, such as liquidparaffin, squalane, vaseline and microcrystalline wax; ester oils, suchas isopropylmyristate, cetyl-2-ethylhexalate,glyceryl-tri-2-ethylhexanoate, vitamin C palpitate, vitamin C stearate,vitamin C sulfate and vitamin E acetate; waxes, such as beeswax andspermaceti; vegetable oils, such as avocado oil, almond oil, rice branoil, olive oil, castor oil, rapeseed oil, saffron oil, corn oil, wheatgerm oil, soybean oil, cotton-seed oil, tea-seed oil and jojoba oil;animal oils, such as turtle oil, mink oil and yolk oil; higher alcohols,such as cetyl alcohol, stearyl alcohol, oleyl alcohol, octyldodecanoland behenyl alcohol; higher fatty acids, such as laurylic acid, myristicacid, palmitic acid, stearic acid, oleic acid, linolic acid, linolenicacid, ricinoleic acid and isostearic acid; silicone oils, such asdimethylsilicone, methylphenylsilicone and cyclic silicone; othersilicone resins and silicone polymers.

The cosmetic composition of the invention may contain polyvalentalcohols, such as ethyleneglycol, propyleneglycol, 1,3-butyleneglycol,dipropyleneglycol, glycerin, and polyglycerins such as diglycerin,triglycerin, tetraglycerin, pentaglycerin and hexaglycerin;trimethylolpropane, 1,2,6-hexatriol, glucose, maltose, maltitol,sucrose, fructose, xylitol, mannitol, sorbitol, maltotriose, threitol,sorbitan, starch-decomposed sugar and starch decomposed reducingalcohol, alone or in combination thereof.

The cosmetic composition of the invention may contain any ingredientscustomarily used in cosmetics and pharmaceutical bases, such ashumectants, active ingredients, fragrances, preservatives, colorants, UVabsorbents, astringents, synthetic surfactants, pigments (e.g., kaolin,mica, sericite, talc, yellow iron oxide, red iron oxide and titaniumoxide) and water.

The cosmetic composition of the invention includes massage creams,cleansing creams, skin creams, foundation creams, makeup bases, haircreams, massage jellys, and medicinal jellys, but is not limited tothose.

The invention will be explained further in detail in reference to thefollowing Examples, but shall not be limited to those.

Preparation of trehalose-6-Fatty Acid Ester

EXAMPLE 1. Preparation of 6-(10-undecylenyl)-trehalose

a) One hundred grams of α, α-trehalose were dissolved in 400 ml ofdimethylformamide, to which added were 52.4 g of methyl 10-undecylenateand 1.0 g of potassium hydroxide, heated to 100° C. and then stirred for12 hours. After this reaction solution was cooled, unreacted methyl10-undecylenate was removed by extracting the solution with 400 ml ofhexane three times. The dimethylformamide solution containing thedesired substance was concentrated to about 200 ml in vacuum, to which,then, 1,000 ml of acetone was added to precipitate unreacted trehalosewhich was subsequently filtered out. The precipitate were washed with100 ml of n-butanol, and the washing liquid was combined with the abovefiltrate. The filtrate was distilled in vacuum to obtain a yellowishviscous syrup. This viscous syrup was subjected to silica gelchromatography (developing solvent: chloroform/methanol=4/1) so as toremove remaining unreacted substances. A fraction containing the desiredsubstance was distilled in vacuum to obtain 24.3 g of a yellowishviscous syrup.

b) The resultant syrup was analyzed by ¹³C-NMR spectroscopy. Signalswere confirmed for a carbonyl group at 175.5 ppm, terminal methylenegroup at 140.11 and 114.73 ppm, and 6- and 6′-positions of trehalose at64.4 and 62.64 ppm. This indicates the formation of6-(10-undecylenyl)-trehalose.

EXAMPLE 2. Preparation of 6-lauroyl-trehalose

The procedures of Example 1a) were repeated with the exception that 62.5g of methyl laurate was used instead of 52.4 g of methyl10-undecylenate. 27.3 g of a white solid were obtained.

The resultant white solid was analyzed by ¹³C-NMR spectroscopy. Signalswere confirmed for a carbonyl group at 175.5 ppm, and 6- and6′-positions of trehalose at 64.4 and 62.64 ppm. The solid was analyzedby FAB-MS spectrometry with NaI and a peak at 547(M(molecular weight ofthe parent peak)+23) was confirmed. These indicate the formation of6-lauroyl-trehalose.

EXAMPLE 3. Preparation of 6-stearoyl-trehalose

The procedures of Example 1a) were repeated with the exception that 87.1g of methyl stearate was used instead of 52.4 g of methyl10-undecylenate. 32.1 g of a white solid was obtained. The resultantwhite solid was analyzed by FAB-MS spectrometry with NaI and a peak at631(M(molecular weight of the parent peak)+23) was confirmed. Thisindicates the formation of 6-stearoyl-trehalose.

EXAMPLE 4. Preparation of trehalose-6-soybean Fatty Acid Ester

One hundred grams of α, α-trehalose were dissolved in 400 ml ofdimethylformamide. To this solution added were 60 g of a methyester ofsoybean fatty acid and 1.0 g of potassium hydroxide, heated to 100° C.,and then stirred for 18 hours. After this reaction solution was cooled,the unreacted methylester of soybean fatty acid was removed byextracting the reaction solution with 400 ml of hexane five times. Thedimethylformamide solution containing the desired substance wasconcentrated to about 200 ml in vacuum, to which 1,500 ml of acetone wasadded to precipitate unreacted trehalose which was subsequently filteredoff. The precipitates were washed with 100 ml of n-butanol, and thewashing liquid was combined with the above filtrate. The filtrate wasdistilled in vacuum to obtain 41.6 g of trehalose-6-soybean fatty acidester as a yellowish viscous syrup, which contained 6-linoleyl-trehaloseas a primary component.

EXAMPLE 5. Preparation of trehalose-6-palm Oil Fatty Acid Ester

The procedures of Example 4 were repeated with the exception that 60 gof a methylester of palm oil fatty acid were used instead of 60 g ofmethylester of soybean fatty acid to obtain 34.9 g of trehalose-6-palmoil fatty acid ester as a yellowish viscous syrup, which contained6-lauroyl-trehalose as a primary component.

Safety Test

As a safety test on the above trehalose-6-fatty acid esters, irritationto skin was examined in accordance with the following procedures.

An adhesive plaster for patch test which had been impregnated with 1 mlof a 0.2% solution of the surfactant was put on 20 subjects for 24hours. Irritation was evaluated 24 hours after removing the patch. Theresult was rated by percentage of positive subjects who showed an clearerythema. The results are as shown in Table 1. Sodium laurylphosphateused as a control is a surfactant which is usually used in shampoos,body shampoos and the like. TABLE 1 Irritation to skin, Sample (0.1%solution) positive, % 6-(10-Undecylenyl)-trehalose 0 6-Lauroyl-trehalose0 6-Stearoyl-trehalose 0 Trehalose-6-soybean fatty acid ester 0Trehalose-6-palm fatty acid ester 0 Control (Monosodium lauryl 0.5phosphate)

As seen from Table 1, the trehalose-6-fatty acid ester of the inventionhas no irritation to skin and has excellent safety to skin.

EXAMPLES 6-8. Preparation of a Skin Washing Agent

Liquid skin washing agents having the compositions shown in Table 2 wereprepared using the 6-(10-undecylenyl)-trehalose, 6-lauroyl-trehalose,trehalose-6-palm oil fatty acid ester prepared above. These washingagents were used to wash face. Soil was removed completely and thefeeling was fine. TABLE 2 Example 6 Example 7 Example 8 Component wt. %wt. % wt. % 6-(10-Undecylenyl)- 25.0 — — trehalose 6-Laurolyl-trehalose— 15.0 — Trehalose-6-palm oil — — 25.0 fatty acid ester Miranol C2M 5.05.0 5.0 (Miranol) Glycerine 10.0 10.0 10.0 Carboxyvinyl polymer 0.6 0.60.6 Perfume (citrus 0.4 0.4 0.4 type composition) Water 59.0 69.0 59.0

EXAMPLES 9 and 10 Preparation of a Hair Washing Agent

Hair washing agents having the compositions shown in Table 3 wereprepared using the 6-(10-undecylenyl)-trehalose or 6-lauroyl-trehaloseprepared above. These washing agents were used to wash hair. Foaming wasexcellent and the feeling was fine. TABLE 3 Example 9 Example 10Component wt. % wt. % 6-(10-Undecylenyl)- 20.0 — trehalose6-Laurolyl-trehalose — 20.0 Palm oil fatty acid 5.0 5.0 diethanol amideCationated cellulose 0.5 0.5 Perfume (fresh floral 0.5 0.5 composition)Water 74.0 74.0

EXAMPLES 11-13 Preparation of Oil-in-Water Skin Creams

Oil-in-water skin creams having the compositions shown in Table 4 wereprepared using the above-prepared 6-(10-undecylenyl)-trehalose,6-stearoyl-trehalose or trehalose-6-soybean fatty acid ester. Thesecreams showed extremely good emulsification, and had fine adaptation toskin without stickiness. TABLE 4 Example 11 Example 12 Example 13Component wt. % wt. % wt. % 6-(10-Undecylenyl)- 1.5 — — trehalose6-Stearoly-trehalose — 1.5 — Trehalose-6-soybean — — 1.5 fatty acidester Glycerol monostearate 2.4 2.4 2.4 Cetylalcohol 4.0 4.0 4.0 Solidparaffin 5.0 5.0 5.0 Squalane 10.0 10.0 15.0 Octyldodecyl 5.0 5.0 —myristearate Glycerine 5.0 5.0 5.0 Perfume (floral 0.1 0.1 0.1composition) Water 67.0 67.0 67.0

Preparation of Cosmetic Compositions

The evaluation for various properties of the cosmetic compositions wasperformed in accordance with the following method.

(1) Long-Term Stability Test

Each sample was placed in a thermostat bath at 45° C. for 1-6 months,and then its appearance was evaluated by the naked eye.

(2) Sensory Properties Test

The sensory properties were evaluated as a whole for feeling onapplication (adaptation to skin) and finishing after application(dampish) by three examiners.

(3) Appearance Testing

The skin surface texture and beauty were evaluated by the naked eye.

(4) Skin Irritating Test

A patch test adhesive plaster which was impregnated with the samplecomposition was put on 20 subjects for 24 hours, and then irritation wasevaluated 24 or 48 hours after the detachment of the adhesive plaster.Individuals who showed clear erythema were regarded as positive. Theresult is indicated as a ratio of the positives.

EXAMPLES 14-17 Preparation of Skin Milks

Skin milks were prepared with the formulations shown in Table 5 usingthe above-prepared 6-lauroyl-trehalose as the trehalose-6-fatty acidester in the following manner. Components 1-5 in Table 5 were mixed anddissolved homogeneously at about 80° C. (Solution 1). Components 6-10and 12 in the Table were mixed and dissolved homogeneously at about 80°C. (Solution 2). The above Solution 2 was then added to Solution 1 understirring with a homomixer to emulsify them, and then the mixture wascooled to room temperature under stirring. During the cooling, Component11 was added at a time when the temperature became 70° C., and furtherthe mixture was cooled to room temperature before stopping the stirring.

Properties of the resultant skin milks are as shown in Table 5. TABLE 5Component Ex. 14 Ex. 15 Ex. 16 Ex. 17 glyceryl monostearate 1.0 1.0 1.01.0 (selfemulsification type) liquid paraffin 10.0 10.0 10.0 10.0squalane 1.0 1.0 1.0 1.0 cholesterol 0.5 0.5 0.5 0.5 cetylalcohol 0.10.1 0.1 0.1 dipropyleneglycol 5.0 5.0 5.0 5.0 glycerine 1.0 1.0 1.0 1.0carboxyvinyl polymer 0.3 0.3 0.3 0.3 6-lauroyl-trehalose 0.1 0.5 1.0 5.0methyl para- 0.2 0.2 0.2 0.2 hydrooxybenzoate perfume 0.2 0.2 0.2 0.2purified water balance balance balance balance Properties long-termstability good good good good (45° C., 4 months) sensory properties(adapting to skin) good good good good (dampish feeling) good good goodgood appearance good good good good irritation to skin 0 0 0 0(positive, %)

As seen from this Table, the skin milks of Examples 14-17 had excellentlong-term stability, sensory properties and appearance, and also had noirritation to skin.

COMPARATIVE EXAMPLES 1-3 Preparation of Skin Milks

Skin milks were prepared with the formulations shown in Table 6 as inExamples 14-17.

The properties of the resultant skin milks are as shown in Table 6.TABLE 6 Component Comp. Ex. 1 Comp. Ex. 2 Comp. Ex. 3glyceryl-monostearate 1.0 1.0 1.0 (selfemulsification type) liquidparaffin 10.0 10.0 10.0 squalane 1.0 1.0 1.0 cholesterol 0.5 0.5 0.5cetylalcohol 0.1 0.1 0.1 dipropyleneglycol 5.0 5.0 5.0 glycerine 1.0 1.01.0 carboxyvinyl polymer 0.3 — 0.3 6-lauroyl-trehalose — 1.0 — sucrosefatty acid ester — — 1.0 methyl para-hydroxybenzoate 0.2 0.2 0.2 perfume0.2 0.2 0.2 purified water balance balance balance Properties long-termstability separated separated good (45° C., 4 months) sensory properties(adapting to skin) bad bad good (dampish feeling) inferior inferior goodappearance bad inferior good irritation to skin 0 0 0.5 (positive, %)

As seen from this Table, Comparative Example 1 which lackedtrehalose-6-fatty acid ester and Comparative Example 2 which lacked awater-soluble polymer had problems in the long-term stability, sensoryproperties and appearance. On the other hand, Comparative Example 3which contained sucrose fatty acid ester which is an emulsifier usuallyused for cosmetics had a problem in the irritation to skin.

EXAMPLES 18-20 AND COMPARATIVE EXAMPLES 4 AND 5

Preparation of Skin Creams

Skin milks were prepared with the formulations shown in Table 7 usingthe above-prepared 6-stearoyl-trehalose as the trehalose-6-fatty acidester in the following manner.

Components 1-7 in Table 7 were mixed and dissolved homogeneously atabout 80° C. (Solution 1). Components 7-9 and 11 in the Table were mixedand dissolved homogeneously at about 80° C. (Solution 2). The aboveSolution 2 was then added to Solution 1 under stirring with a homomixerto emulsify them, and subsequently the mixture was cooled to roomtemperature under stirring. During the cooling, Component 10 was addedat a time when the temperature became 70° C., and further the mixturewas cooled to room temperature before stopping the stirring.

Properties of the resultant skin creams are as shown in Table 7. TABLE 7Component Ex. 18 Ex. 19 Ex. 20 Comp. 4 Comp. 5 olive oil 5.0 5.0 5.0 5.05.0 liquid paraffin 15.0 15.0 15.0 15.0 15.0 beeswax 2.0 2.0 2.0 2.0 2.0cetylalcohol 8.0 8.0 8.0 8.0 8.0 glycelyl 3.0 3.0 3.0 3.0 3.0monostearate white vaseline 3.0 3.0 3.0 3.0 3.0 6-stearoly 1.0 1.0 1.01.0 — -trehalose xanthan gum 0.01 0.5 1.0 — 10.0 methyl para-hydroxy-0.3 0.3 0.3 0.3 0.3 benzoate perfume 0.1 0.1 0.1 0.1 0.1 purified waterbalance balance balance balance balance Properties long-term stabilitygood good good separated separated (45° C., 6 months) sensory properties(adapting to skin) good good good good bad (dampish feeling) good goodgood good inferior appearance property good good good good badirritation to skin 0 0 0 0 0 (positive, %)

As seen from this Table, the skin creams of Examples 18-20 had excellentlong-term stability, sensory properties and appearance, and also had noirritation to skin. On the other hand, Comparative Example 5 whichlacked trehalose-6-fatty acid ester had problems in long-term stability,sensory properties and appearance. Comparative Example 4 which lacked awater-soluble polymer had a problem in long-term stability.

EXAMPLE 21 Preparation of a Makeup Base

A makeup base was prepared with the following formulation. Trehalosemonoisostearate used in this example was synthesized from trehalose andmethyl isostearate as in Example 1.

Formulation: Component  1. liquid paraffin 12.0  2. squalane 3.0  3.glycelol monostearate 1.5  4. cholesterol 0.2  5. cetylalcohol 0.5  6.trehalose monoisostearate 1.5  7. glycerin 5.0  8. carageenan 0.5  9.methyl para-hydoxybenzoate 0.3 10. xthantan gum 1.0 11.dipropyleneglycol 0.8 12. titanium oxide 0.5 13. perfume 0.1 14.purified water balance

The oil components 1-6 in the above formulation were mixed and dissolvedat about 80° C. (Solution 1). The aqueous components 7-10 and 14 weremixed and melted at about 80° C. (Solution 2). Also, Component 12 wasdispersed in Component 11 (Dispersion). The above Solution 2 was thenadded to Solution 1 under stirring with a homomixer to emulsify them.Subsequently, Dispersion 1 was added to the mixture and stirred. Themixture was cooled to room temperature under stirring. During thecooling, Component 13 was added at a time when the temperature become70° C., and further the mixture was cooled to room temperature beforestopping the stirring.

The makeup base thus prepared was an oil-in-water emulsion. After4-month storage in a thermostat bath at 45° C. it had extremely goodstability and also had good sensory properties (adapting to skin,dampish feeling) and good appearance (surface texture).

EXAMPLE 22 Preparation of a Hair Cream

A hair cream was prepared with the following formulation. Trehalosemonodocosanate used in this example was synthesized from trehalose andmethyl docosanate as in Example 1.

Formulation: Component  1. stearic acid 0.5  2. squalane 2.0  3. liquidparaffin 40.0  4. glycelol monostearate 0.5  5. dimethylpolysiloxane 1.0 6. butyl para-hydoxybenzoate 0.1  7. trehalose monodocosanate 2.0  8.propyleneglycol 2.0  9. sorbitol 3.0 10. glycerin 3.0 11.methylcellulose 0.3 12. tetra-sodium edetate 0.1 13. methylpara-hydoxybenzoate 0.2 14. sodium chondroitin sulfate 0.3 15. perfume0.3 16. purified water balance

The oil components 1-7 in the above formulation were mixed and dissolvedat about 80° C. (Solution 1). The aqueous components 8-14 and 16 weremixed and melted at about 80° C. (Solution 2). The above Solution 2 wasthen added to Solution 1 under stirring with a homomixer to emulsifythem, and cooled to room temperature under stirring. During the cooling,Component 15 was added-just at a time when the temperature became 70°C., and further the mixture was cooled to room temperature beforestopping the stirring.

The hair cream thus obtained had extremely good stability after 6-monthstorage in a thermostat bath at 45° C. It had also good sensoryproperties (adapting to skin, dampish feeling) and good appearance(surface texture).

EXAMPLE 23 Preparation of a Cleansing Cream

A cleansing cream was prepared with the following formulation. Thetrehalose monolinoleate and the trehalose monocaprate used in thisExample were synthesized from trehalose and methyl linolenate or methylcaprate as in Example 1.

Formulation: Component  1. beeswax 5.0  2. cetylalcohol 2.0  3. liquidparaffin 15.0  4. vaseline 17.0  5. glycelol monostearate 3.0  6.dimethylpolysiloxane 3.0  7. butyl para-hydoxybenzoate 0.1  8. trehalosemonolinoleate 3.0  9. trehalose monocaprate 3.0 10. sodiumN-stearoyl-L-glutamate 2.0 11. glycerin 4.0 12. methylpara-hydoxybenzoate 0.3 13. dipropyleneglycol 2.0 14.polyvinylpyrrolidon 2.0 15. purified water balance

The oil components 1-8 in the above formulation were mixed and dissolvedat about 80° C. (Solution 1). The aqueous components 9-15 were mixed andmelted at about 80° C. (Solution 2). The above Solution 2 was then addedto Solution 1 under stirring with a homomixer to emulsify them, andcooled to room temperature under stirring. After that, the stirring wasstopped.

The cleansing cream thus prepared had extremely good stability after6-month storage in a thermostat bath at 45° C. It had also good sensoryproperties (adapting to skin, dampish feeling) and good appearance(surface texture).

EXAMPLE 24 Preparation of a Massage Jelly

A massage jelly was prepared with the following formulation.

Formulation: Component  1. squalane 10.0  2. olive oil 4.0  3. vitamin Eacetate 0.2  4. liquid paraffin 8.0  5. polyoxyethylene cetylether (2E.O) 2.0  6. trehalose monolaurate 2.0  7. glycerin 35.0  8.dipropyleneglycol 20.0  9. polyvinylalcohol 18.0 10. dipotassiumglycyrrhizeinate 0.1 11. purified water balance

The oil components 1-6 in the above formulation were mixed and dissolvedat about 80° C. (Solution 1). The aqueous components 7-11 were mixed andmelted at about 80° C. (Solution 2). The above Solution 2 was then addedto Solution 1 under stirring with a homomixer, and the mixture wascooled to room temperature under stirring. After that, the stirring wasstopped.

The massage jelly thus prepared had extremely good stability after6-month storage in a thermostat bath at 45° C. It had also good sensoryproperties (adapting to skin, dampish feeling) and good appearance(surface texture).

EXAMPLE 25 Preparation of a Cleansing Gel

The cleansing gel was prepared with the following formulation. Trehalosemonomyristate used in this Example was synthesized from trehalose andmethyl myristate as in Example 1.

Formulation: Component 1. 2-ethyl hexanoic acid triglyceride 5.0 2.olive oil 41.0 3. liquid paraffin 15.0 4. dimethylpolysiloxan 2.0 5.glycerin 20.0 6. trehalose monolaurate 7.0 7. trehalose monomyristate2.0 5. polyoxyethylenesorbitan monolaurate(20 E.O.) 2.0 9. carboxyvinylpolymer 0.7 10. purified water balance

The oil components 1-4 in the above formulation were mixed and dissolvedat about 80° C. (Solution 1). The aqueous components 5-10 were mixed andmelted at about 80° C. (Solution 2). The above Solution 2 was then addedto Solution 1 under stirring with a homomixer, and the mixture wascooled to room temperature under stirring. After that, the stirring wasstopped.

The cleansing gel thus prepared had extremely good stability after6-month storage in a thermostat bath at 45° C. It had also good sensoryproperties (adapting to skin, dampish feeling) and good appearance(surface texture).

The present invention relates also to a liposome which is characterizedin that it has a wall membrane formed from trehalose fatty acid esterand which is useful in drugs, quasi-drugs cosmetics and so forth.

Liposome is a closed vesicle whose wall membrane is composed of a lipidbilayer. Natural biomembrane is said to have lipid dyad membranestructure. The present liposome has biomembrane-like structure.Therefore, it is expected that the liposome has high affinity withbiocell membrane and has high potential as a drug carrier. Recently, thedevelopment of liposome formulations aiming at a drug delivery systemhas been desired not only in the fields of pharmaceuticals, but incosmetics.

Phospholipid (lecithin) has been used as a liposome forming agent. Thisis excellent in safety, but is hardly used in practical applicationsbecause of its poor chemical and physical stabilities. In other words,chemical changes such as changes of color and smell occur in long-termstorage in the case where liposome is prepared with phospholipid. Also,physical changes such as aggregation and precipitation occur afterlong-term storage or by rehydration after freeze-drying. Because ofthese problems, liposomes from phospholipid have not been put topractical use.

It was tried to find other substance which has liposome-forming activityto solve these problems. For example, there are publications ondialkyl-type cationic surfactants such as dialkyldimethylammoniumchloride (kunitake et al. J. Am. Chem. Soc., vol 99, pp 860, 1977),POE-type nonionic surfactants such as polyoxyethylene cured castor oil(Japanese Patent Application Laid Open No. 52-6375/1977, and No.59-16534/1984). Also, there are reported sucrose fatty acid esters(Japanese Patent Application Laid Open No. 61-207324/1986), glucosefatty acid esters (Japanese Patent Application Laid Open No.4-300820/1991), and glucose alkylether (Japanese Patent Application LaidOpen No. 59-106423/1984), in which sugars are used as a hydrophilicgroup. However, the stability of these liposomes is not satisfactory.

Also, in order to improve the stability of liposome, sugars such astrehalose are added to liposome (Japanese Patent Application Laid OpenNo. 62-500102/1987, and No. 62-501631/1987). However, there is no reportin which trehalose fatty acid ester is used as a liposome forming agent.

Meanwhile, there are some report on trehalose fatty acid ester, such asa report on its synthesis (Chem. Pharm. Bull, 30(4), pp 1169-1174(1982),a report aiming to use trehalose difatty acid ester as a surfactant(Japanese Patent Application Laid Open No. 60-258195/1985 and No.62-91236/1987), and a report aiming to use it as an antitumor agent(Japanese Patent Application Laid Open No. 61-289038/1986, Chem. Pharm.Bull., vol 25(7), pp 1717-1724). However, there is no report whichdiscloses or suggests the liposome forming activity.

A further object of the invention is to provide a liposome which hasexcellent chemical and physical stabilities such as storage stability.

The present invention is a liposome, characterized in that it hasmembrane wall composed of a trehalose fatty acid ester.

The present invention is a liposome, characterized in that it hasmembrane wall composed of trehalose difatty acid ester.

The present invention will be explained further in details below.

The trehalose fatty acid ester used in the invention can be obtainedfrom trehalose and a fatty acid or ester thereof in a known synthesismethod, such as by ester exchange reaction between trehalose and a loweralkyl ester of a fatty acid.

The trehalose fatty acid ester can be produced, for example, in a methodfor the preparation of sucrose fatty acid esters disclosed in U.S. Pat.No. 2,893,990 and No. 3963699, Japanese Patent Application Laid OpenNo36-21717/1961 and No. 53-6130/1978, all of which are incorporatedherein by reference.

Trehalose may be any of α, α-trehalose, α, β-trehalose or β, β-trehaloseor mixtures of two or more of them.

In these methods, a mixture of mono-fatty acid ester, di-fatty acidester and tri- or more fatty acid ester of trehalose are obtained asreaction products. These products can be isolated by any conventionalpurification methods. However, the mixture of trehalose fatty acid estercan be used without any purification.

As the trehalose fatty acid ester, preferred are trehalose poly-fattyacid esters, particularly diesters. The fatty acid to compose thetrehalose fatty acid ester is preferably those having 8-22 carbon atoms,particularly saturated or unsaturated higher fatty acids having 10-18carbon atoms. Examples of those include trehalose caprylate, trehalosenonanate, trehalose caprate, trehalose undecanate, trehalose laurate,trehalose myristate, trehalose palmitate, trehalose stearate, trehalosearachidonaeate, trehalose docosanate, trehalose undecylenate, trehaloseoleate, trehalose linolate, trehalose linolenate, trehalose isostearate,trehalose monohydroxystearate, and trehalose ricinoleate. These fattyacids may be used alone or as a mixture. The diesters are not requiredto be of high purity, and the content of the diesters is preferably 30wt. % or more, based on the total weight of the trehalose fatty acidester.

The liposome of the invention may contain unreacted raw materials, i.e.trehalose and fatty acid esters in such an amount as not to adverselyaffect the liposome formation.

The liposome of the invention may be composed of a single species oftrehalose fatty acid ester or a mixture of two or more species.

The liposome of the invention may contain sterols, such as cholesteroland cholestanol, as a membrane stabilizer; dicetylphosphate,phosphatidic acid, ganglioside, stearylamine and so forth, as a chargedsubstance; and α-tocopherol as an antioxidant. These substances may beadded preferably in amounts of about 0.01 to about 2.0 weight parts perweight part of the trehalose fatty acid ester, but not limited to such arange.

Any conventional methods for preparing a liposome can be used in theinvention. For example, a vortexing method, a sonication method, apre-vesicle method, an ethanol injection method, a French press method,an ether injection method, an annealing method, a W/O/W emulsion method,a reverse phase evaporation method and so forth can be mentioned. Any ofthem or any combination of them can be used, but not limited to these.

Preparation in a vortexing method or sonication method will be explainedbelow.

A trehalose fatty acid ester and a membrane stabilizer and any optionalsubstances are dissolved in an organic solvent, preferably chloroform,and the organic solvent was evaporated out to form a thin membranecomposed of the trehalose fatty acid ester. A buffer solution in which awater-soluble component, etc. were dissolved was added, and was vortexedat or above its phase transition temperature to strip off the membrane.At this point of time, a polylayer liposome (MLV) was formed. Then, asingle layer liposome (SUV) was obtained by sonication, if desired.

The liposome of the invention may contain ordinary pharmaceuticalcomponents such as water-soluble polymers, polyvalent alcohols,preservatives and chelating agents.

EXAMPLES

This invention will be explained further in details in the followingExamples, but not limited to those.

Example A

One hundred mg of trehalose dilaurate was charged in a 50 ml volumeeggplant type flask, and dissolved by adding 5 ml of chloroform. Then,this flask was set on a rotary evaporator, and the solvent wasevaporated out slowly so that a thin membrane of trehalose dilaurate wasformed on the inner wall of the flask. The inside of the flask was thenevacuated by a vacuum pump to be dried for additional 3 hours. Fourmillilitres of distilled water were added and shaked at 60° C. tostrip-off the thin membrane. Thus, an aqueous cloudy liquid wasobtained. In observation by a polarizing microscope (x 400), particlesof 1-10 μm in diameter were seen with “closed lamella structure” whichis characteristic of MLV. This aqueous liquid was stained withphosphotungstic acid. In observation by a transmission electronmicroscope (×100,000), closed vesicles having about five- to nine-layermembrane structure, i.e., liposomes, were observed. Then, this aqueousliquid was sonicated by a probe-type sonicator for 10 min. at 60° C. Inobservation by a transmission electron microscope as above, SUV's of50-80 nm in particle diameter were observed.

Example B

Liposomes were prepared in accordance with the procedures of Example Aexcept that a 100 mM aqueous carboxyfluorescein (CF) solution wassubstituted for distilled water. After MLV's were formed, a liposomesolution was gel filtrated to remove CF present in the exterior phase(i.e., not contained in liposomes). Then, liposomes were destroyed byadding an aqueous Triton X-100 solution. By measuring the fluorescenceintensities before and after the addition of the aqueous Triton X-100solution, it was confirmed that CF was trapped in the interior phase(inside the liposomes). The retaining efficiency was 15.5%.

Example C

Liposomes were prepared in accordance with the procedures of Example Aexcept that trehalose dipalmitate was substituted for trehalosedilaurate. In observation by an electron microscope, it was confirmedthat MLV's and SUV's were formed.

Example D

A mixture of 20 mg of trehalose monomyristate, 60 mg of trehalosedistearate and 20 mg of trehalose tri- or more stearate was added to 8ml of ethanol and dissolved by heating at 50° C. The solution waspressure injected into distilled water heated at 60° C. by a syringe. Asa result, an aqueous translucent solution was obtained. In observationby an electron microscope as in Example A, it was confirmed that SUV'swere formed.

The results of Examples A-D showed that trehalose fatty acid esterscould form liposomes.

In the following, the liposome of the invention was compared with theliposome of prior art for stability.

Example E

One gram of Trehalose diundecylenate, 0.5 g of cholesterol and 0.2 g ofdicetylphosphate were charged in a 200 ml volume eggplant type flask anddissolved by adding 10 ml of chloroform. Then, this flask was set on arotary evaporator, and the solvent was evaporated out slowly so that athin membrane was formed on the inner wall of the flask. The inside ofthe flask was then evacuated by a vacuum pump to be dried for additional3 hours. One hundred millilitres of distilled water were added andshaked at 60° C. to strip off the thin membrane. Then, this solution wassonicated by a probe-type sonicator for 10 min. at 60° C. to prepareSUV's. In observation by a dynamic light scattering method, the particlediameter was 62 nm.

Example F

A mixture of 0.2 g of trehalose monomyristate, 0.6 g of trehalosedistearate and 0.2 g of trehalose tri- or more stearate was added to 10ml of ethanol and dissolved by heating at 50° C. The solution waspressure injected into distilled water heated at 60° C. by a syringe toprepare SUV's. In observation by a dynamic light scattering method, theparticle diameter was 73 nm.

Comparative Example A

SUV's were prepared in accordance with the procedures of Example Eexcept that hydrogenated soybean lecithin was substituted for trehalosediundecylenate. In observation by a dynamic light scattering method, theparticle diameter was 59 nm.

Comparative Example B

SUV's were prepared in accordance with the procedures of Example Eexcept that sucrose diundecylenate was substituted for trehalosediundecylenate. In observation by a dynamic light scattering method, theparticle diameter was 70 nm.

After storing the liposomes which were prepared in Examples E and F andComparative Examples A and B for 3 months at 40° C., the changes ofcolor, smell and particle diameter were examined. The results are asshown in Table A.

Further, the liposomes were each freeze-dried and re-hydrated, and thentheir particle diameters were measured. The results are as shown inTable B. TABLE A Conditions after 3 Month-Storage at 40° C. particlediameter, color change foul smell nm Example E no no 75 Example F no no80 Comp. Ex. A yellowish egg smell 159 Comp. Ex. B no no 142

TABLE B Particle Diameter After Freeze-Drying and Re- Hydration particlediameter, nm Example E 72 Example F 77 Comp. Ex. A 189 Comp. Ex. B 112

Tables A and B show that the liposomes of the invention showed superiorstability compared with the liposomes of the prior art prepared fromhydrogenated soybean lechitin or sucrose fatty acid ester.

The results of Examples E and F were better than those of ComparativeExample B. The reason of these results is considerably that themolecular structure of trehalose diundecylenate is more symmetrical thanthat of sucrose diundecylenate, which contributes to the stability ofthe liposomes.

The liposome of the invention has excellent stability. Also, theliposome of the invention can properly envelop water-soluble oroil-soluble drugs and does not suffer from chemical and physicalchanges. Therefore, the liposome of the invention is useful in thefields of drugs, quasi-drugs, cosmetics and so forth, and can provideliposome formulations suitable for injection drugs, oral medicines,external medicines, lotions, emulsions, creams, essences, and hairtonics.

1. A surfactant comprising at least one trehalose-6-fatty acid esterrepresented by the following formula:

wherein R represents a saturated or unsaturated acyl group having 8-22carbon atoms, and may have a hydroxy group or other substituents.
 2. Asurfactant comprising at least one trehalose-6-fatty acid estersselected from the group consisting of 6-(10-undecylenyl)-trehalose,6-lauroyl-trehalose, 6-stearoyl-trehalose, trehalose monoisostearate,trehalose monodocosanate, trehalose monolinoleate, trehalosemonocaprate, and trehalose monomyristate.
 3. A washing agent comprisingthe surfactant as claimed in claim
 1. 4. The washing agent as claimed inclaim 3, wherein the washing agent is a hair or skin washing agent. 5.The washing agent as claimed in claim 3, wherein a content of saidtrehalose-6-fatty acid ester is 1-50 wt. %, preferably 10-35 wt. %. 6.An emulsion-type cosmetic composition comprising at least onewater-soluble polymer selected from trehalose-6-fatty acid estersrepresented by the following formula:

wherein R represents a saturated or unsaturated acyl group having 8-22carbon atoms, and may have a hydroxyl group or other substituents.
 7. Anemulsion-type cosmetic composition comprising at least onetrehalose-6-fatty acid ester selected from the group consisting of6-(10-undecylenyl)-trehalose, 6-lauroyl-trehalose, 6-stearoyl-trehalose,trehalose monoisostearate, trehalose monodocosanate, trehalosemonolinoleate, trehalose monocaprate, and trehalose monomyristate, and awater-soluble polymer.
 8. The emulsion-type cosmetic composition asclaimed in claim 6, wherein said water-soluble polymer is one or more ofwater-soluble polymers selected from the group consisting of guar gum,roastbean gum, queensseed, carageenan, galactan, arabic gum, tragacanth,pectin, mannan, starch, xanthan gum, dextrin, succinoglucan, curdlan,gelatin, casein, albumin, collagen, methyl cellulose, ethyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, methylhydroxypropyl cellulose, soluble starch, carboxymethylstarch, methyl starch, propyleneglycol alginate, salts of alginic acid,polyvinylalcohol, polyvinylpyrrolidone, polyvinylmethylether,carboxyvinyl polymers, sodium polyacrylate, polyethyleneglycol, ethyleneoxide/propylene oxide copolymers, cationated cellulose, sodiumchondroitin sulfate and sodium hyaluronate.
 9. The emulsion-typecosmetic composition as claimed in claim 6, wherein a content of saidtrehalose-6-fatty acid ester is 0.01-20 wt. %, preferably 0.1-10 wt. %and a content of said water-soluble polymer is 0.001-40 wt. %,preferably 0.01-20 wt. %.
 10. The emulsion-type cosmetic composition asclaimed in claim 6, wherein said emulsion-type cosmetic composition is amassage cream, a cleansing cream, a skin cream, a foundation cream, amakeup base, a hair cream, a massage jelly or a medicinal jelly.
 11. Aliposome comprising a membrane wall composed of a trehalose fatty acidester.
 12. The liposome as claimed in claim 11, wherein said trehalosefatty acid ester is trehalose difatty acid ester.
 13. The liposome asclaimed in claim 11, wherein fatty acid of which said trehalose fattyacid ester is constituted is a saturated or unsaturated fatty acid whichhas 8-22 carbon atoms, preferably 10-18 carbon atoms, and may have ahydroxyl group or other substituents.
 14. A liposome comprising amembrane wall mainly composed of at least one trehalose fatty acid esterselected from the group consisting of trehalose dilaurate, trehalosedipalmitate, trehalose diundecylenate, trehalose dimyristate andtrehalose distearate.